Benzimidazole compounds for regulating IgE

Abstract

This invention relates to a family of phenylbenzimidazole analogs, which are inhibitors of the IgE response to allergens. These compounds are useful in the treatment of allergy and/or asthma or any diseases where IgE is pathogenic.

1 . A compound selected from Formula A or B:  
     
       
         
         
             
             
         
       
       wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF 3 , OCF 3 , CONH 2 , CONHR, NHCOR 1 , benzo, COPh, COOCH 3 , and NHCONHCR 1 ;  
       wherein R is selected from the group consisting of H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , CH 2 Ph, and CH 2 C 6 H 4 —F(p-);  
       wherein R 1  and R 2  are independently selected from the group consisting of alkyl, substituted alkyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, substituted bicycloheptyl, bicyclooctyl, bicyclononyl, bicycloalkenyl, substituted bicycloalkenyl, adamantyl, substituted adamanyl, heterocyclic rings, and substituted heterocyclic rings; and  
       wherein the substituents on R 1  or R 2  are selected from the group consisting of alkyl, acyl, aryl, carbonyl, CF 3 , CH 3 , OCH 3 , OH, CN, COOR, COOH, COCF 3 , and heterocyclic rings;  
       wherein R 1  and R 2  cannot both be methyl.  
     
   
   
       2 . A compound of Formula A:  
     
       
         
         
             
             
         
       
       wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF 3 , OCF 3 , CONH 2 , CONHR and NHCOR 1 ;  
       wherein R is selected from the group consisting of H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , CH 2 Ph, and CH 2 C 6 H 4 —F(p-);  
       wherein R 1  and R 2  are independently selected from the group consisting of alkyl, substituted alkyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, substituted bicycloheptyl, bicyclooctyl, bicyclononyl, bicycloalkenyl, substituted bicycloalkenyl, adamantyl, and substituted adamantyl, wherein said substituents are not heterocyclic rings; and  
       wherein the substituents on R 1  or R 2  are selected from the group consisting of alkyl, aryl, carbonyl, CF 3 , CH 3 , OCH 3 , OH, CN, COOR, and COOH.  
     
   
   
       3 . The compound of  claim 2  selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       4 . A compound selected from Formula A or B:  
     
       
         
         
             
             
         
       
       wherein X and Y are independently selected from the group consisting of H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF 3 , OCF 3 , CONH 2 , CONHR, and NHCOR 1 ;  
       wherein R is selected from the group consisting of H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , CH 2 Ph, and CH 2 C 6 H 4 —F(p-);  
       wherein R 1  and R 2  are independently selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, bicyclooctyl, bicyclononyl, substituted bicycloalkenyl, adamantyl, substituted adamantyl, heterocyclic rings, and substituted heterocyclic rings;  
       wherein R 1  and R 2  cannot both be methyl groups;  
       wherein the substituents on R 1  or R 2  are selected from the group consisting of alkyl, acyl, aryl, CF 3 , CH 3 , OCH 3 , OH, CN, COOR, COOH, COCF 3 , and heterocyclic rings; and  
       wherein at least one of R 1 , R 2  or said substituents is a heterocyclic ring; and  
       
         
           
           
               
               
           
         
       
       wherein X is selected from the group consisting of mono, di, tri, and tetra substituted H, alkyl, alkoxy, aryl, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF 3 , OCF 3 , CONH 2 , CONHR, and NHCOR 1 ;  
       wherein R is selected from the group consisting of H, CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , CH 2 Ph, and CH 2 C 6 H 4 —F(p-);  
       wherein Y is selected from the group consisting of mono, di, tri, and tetra substituted H, alkyl, alkoxy, aryl, benzo, substituted aryl, hydroxy, halogen, amino, alkylamino, nitro, cyano, CF 3 , OCF 3 , COPh, COOCH 3 , CONH 2 , CONHR, NHCONHR 1 , and NHCOR 1 ; and  
       wherein R 1  is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, multi-ring cycloalkyl, fused-ring aliphatic, cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, cycloheptyl, substituted cycloheptyl, bicycloheptyl, bicyclooctyl, bicyclononyl, substituted bicycloalkenyl, adamantyl, substituted adamantyl, heterocyclic rings containing one or more heteroatoms, and substituted heterocyclic rings; and  
       wherein the substituents on R 1  are selected from the group consisting of alkyl, aryl, CF 3 , CH 3 , OCH 3 , OH, CN, COOR, COOH, and heterocyclic rings.  
     
   
   
       5 . The compound of  claim 4 , wherein the compound is from Formula A.  
   
   
       6 . The compound of  claim 4 , wherein the compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
   
   
       7 . The compound of  claim 4 , wherein the compound is from Formula B.  
   
   
       8 . The compound of  claim 4 , wherein the compound is selected from the group consisting of:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       9 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
   
   
       10 . A compound having the formula:  
     
       
         
         
             
             
         
       
     
   
   
       11 . The compound of  claim 1 , further comprising at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.  
   
   
       12 . The compound of  claim 11 , wherein said at least one additional ingredient is selected from the group consisting of a short-acting β 2 -adrenergic agonist, a long-acting β 2 -adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.  
   
   
       13 . A method for treating or preventing an allergic reaction in a mammal wherein said reaction is caused by an increase in IgE levels comprising administering an IgE-suppressing amount of at least one compound of  claim 1 .  
   
   
       14 . The method of  claim 13 , further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.  
   
   
       15 . The method of  claim 14 , wherein said additional ingredient is selected from the group consisting of a short-acting β 2 -adrenergic agonist, a long-acting β 2 -adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.  
   
   
       16 . A method for treating or preventing asthma in a mammal comprising administering an IgE-suppressing amount of at least one compound of  claim 1 .  
   
   
       17 . The method of  claim 16  further comprising administering at least one additional ingredient which is active in reducing at least one symptom associated with said allergic reaction.  
   
   
       18 . The method of  claim 17 , wherein said additional ingredient is selected from the group consisting of a short-acting β 2 -adrenergic agonist, a long-acting β 2 -adrenergic agonist, an antihistamine, a phosphodiesterase inhibitor, an anticholinergic agent, a corticosteroid, an inflammatory mediator release inhibitor and a leukotriene receptor antagonist.